Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor and psychiatric symptoms. Accumulating evidence has implicated mitochondrial dysfunction as a hallmark of PD; however, its underlying mechanisms, and particularly the role of individual mitochondrial complex I subunits in disease pathogenesis, remain poorly understood.

In a recent study published in Genes & Diseases, researchers from The First Affiliated Hospital of Chongqing Medical University and Shenzhen Longgang District Maternity & Child Healthcare Hospital integrated bioinformatics analyses with experimental validation, both in vitro and in vivo, to investigate the role of NDUFA11 in Parkinson's disease.

Using transcriptomic data from multiple datasets, the authors screened differentially expressed genes (DEGs) between patients with Parkinson's disease and healthy controls. By intersecting these results with the MitoCarta 3.0 database, eight mitochondrial hub genes were identified: NDUFA11, NDUFA8, NDUFA9, NDUFA1, NDUFB1, NDUFS7, COX7B, and COX14. Further analysis revealed that NDUFA11 (NADH Oxidoreductase Subunit A11), an accessory subunit essential for the structural integrity and activity of mitochondrial complex I, was a significantly dysregulated mitochondrial gene associated with PD and that its dysregulation was linked to pathways governing mitochondrial respiration, oxidative phosphorylation, and neuronal survival. These findings suggested that impaired NDUFA11 function may contribute to mitochondrial dysfunction in PD.

In this study, the authors employed three PD models, including an MPP⁺-induced MN9D cell line, an MPTP-induced mouse model, and A53T α-synuclein transgenic mice. Experimental validation in both the MPP⁺-induced cellular models and the mouse models supported the bioinformatics results, demonstrating an increase in NDUFA11 protein levels in the substantia nigra of both MPTP-induced mice and A53T mice, accompanied by motor impairment in MPTP-induced mice. Additionally, the mRNA levels of NDUFB1, NDUFS7, and COX14 were also found to be upregulated in the MPP+-treated MN9D cells. Similarly, the authors observed an increase in the protein levels of NDUFA11, NDUFB1, and NDUFS7 in the mouse models.

Knockdown of endogenous NDUFA11 was associated with increased oxidative stress and excessive generation of reactive oxygen species (ROS), indicating that loss of NDUFA11 disrupts mitochondrial homeostasis. NDUFA11 knockdown also aggravated mitochondrial membrane-potential loss and further reduced tyrosine hydroxylase (TH) abundance in the MPP⁺-induced MN9D cells.

Additionally, NDUFA11 expression was positively associated with immature dendritic cells, activated CD8⁺ T cells, natural killer cells, CD56 bright natural killer cells, T follicular helper cells, plasmacytoid dendritic cells, and type 1 T helper cells.

Rescue experiments further demonstrated that exogenous overexpression of NDUFA11 reversed the effects of NDUFA11 knockdown, highlighting its protective role in maintaining mitochondrial integrity. These findings position NDUFA11 not merely as a marker of mitochondrial dysfunction but as an active regulator of neuronal survival whose loss may exacerbate mitochondrial and neuronal abnormalities.

Collectively, this study identifies NDUFA11 as a previously underappreciated mitochondrial factor associated with PD, linking NDUFA11 dysregulation with mitochondrial dysfunction, oxidative stress, and PD-related pathological changes. By integrating transcriptomic analyses with in vitro and in vivo validation, the authors demonstrate that NDUFA11-mediated mitochondrial homeostasis may warrant further investigation as a potential therapeutic target in PD.

Reference

Title of the original paper: Deciphering the role of mitochondrial NDUFA11 in Parkinson's disease: An integrated study of bioinformatics and A53T mouse model
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2026.102277

Funding Information:
National Natural Science Foundation of China (No. 8247050942)
Chongqing Natural Science Foundation Joint Fund for Innovation and Development (China) (No. CSTB2023NSCQ-LZX0041)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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